Arylcycloalkyl derivatives having branched side chains, processes for their preparation and their use as pharmaceuticals

ABSTRACT

Arylcycloalkyl derivatives having branched side chains, processes for their preparation and their use as pharmaceuticals  
     The invention relates to arylcycloalkyl derivatives having branched side chains and to their physiologically acceptable salts and physiologically functional derivatives.  
     What is described are compounds of the formula I,  
                 
 
     in which the radicals are as defined, and their physiologically acceptable salts and processes for their preparations. The compounds are suitable for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders as well as of disorders in which insulin resistence is involved.

DESCRIPTION

[0001] The invention relates to arylcycloalkyl derivatives havingbranched side chains and to their physiologically acceptable salts andphysiologically functional derivatives.

[0002] Compounds of a similar structure have already been described inthe prior art for the treatment of hyperlipidemia and diabetes (WO2000/64876).

[0003] The invention was based on the object of providing compoundswhich permit therapeutically utilizable modulation of lipid and/orcarbohydrate metabolism and are thus suitable for the prevention and/ortreatment of diseases such as type 2 diabetes and atherosclerosis andthe diverse sequelae thereof.

[0004] A series of compounds which modulate the activity of PPAreceptors has surprisingly been found. The compounds are suitable inparticular for activating PPARalpha and PPARgamma, it being possible forthe extent of the relative activation to vary depending on thecompounds.

[0005] Accordingly, the invention relates to compounds of the formula I

[0006] wherein

[0007] ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl,wherein one or more carbon atoms in said (C3-C8)-cycloalkanediyl and(C3-C8)-cycloalkenediyl groups are optionally replaced by oxygen atoms;

[0008] R is NR1R2 or OR1, (C6-C10)-aryl or (C5-C12)-heteroaryl, whereinsaid (C5-C12)-heteroaryl group contains one, two or three identical ordifferent heteroatoms selected from the group consisting of N, O and S;

[0009] R1, R2 are each independently H, (C1-C6)-alkyl,(C3-C8)-cycloalkyl or (C6-C10)-aryl, wherein said (C6-C10)-aryl isoptionally substituted by F, Cl or (C1-C4)-alkyl;

[0010] R3 is (C3-C6)-cycloalkyl or (C1-C10)-alkyl, wherein each group isoptionally substituted by phenyl, pyridyl, morpholinyl or(C3-C6)-cycloalkyl, and wherein said phenyl substituent is optionallysubstituted by chlorine or (C1-C4)-alkyl;

[0011] X is (C1-C6)-alkanediyl, wherein one or more carbon atoms thereinare optionally replaced by oxygen atoms;

[0012] Y is (C1-C6)-alkanediyl, wherein one or more carbon atoms thereinare optionally replaced by oxygen atoms;

[0013] R4 is H or (C1-C4)-alkyl;

[0014] R5 is (C1-C4)-alkyl;

[0015] and pharmaceutically acceptable salts thereof.

[0016] Preference is given to compounds of the formula I whereinsubstituents X and Y are linked to ring A in position 1,3 (X-ring A-Y).

[0017] Preference is furthermore given to compounds of the formula Iwherein:

[0018] ring A is (C3-C8)-cycloalkane-1,3-diyl or(C3-C8)-cycloalkene-1,3-diyl;

[0019] R is NR1R2 or (C6-C10)-aryl;

[0020] R1, R2 are each independently H, (C1-C6)-alkyl,(C3-C8)-cycloalkyl or (C6-C10)-aryl, wherein said (C6-C10)-aryl group isoptionally substituted by F, Cl or (C1-C4)-alkyl;

[0021] R3 is (C3-C6)-cycloalkyl or (C1-C8)-alkyl, wherein each group isoptionally substituted by phenyl, pyridyl, morpholinyl,(C3-C6)-cycloalkyl, and wherein said phenyl substituent is optionallysubstituted by chlorine or methyl;

[0022] X is (C1-C3)-alkanediyl, wherein one carbon atom therein isoptionally replaced by an oxygen atom;

[0023] Y is (C1-C3)-alkanediyl, wherein the carbon atom adjacent to ringA in said (C1-C3)-alkanediyl group is optionally replaced by an oxygenatom;

[0024] R4 is H;

[0025] R5 is methyl;

[0026] and pharmaceutically acceptable salts thereof.

[0027] Particular preference is given to compounds of the formula Iwherein:

[0028] ring A is cyclohexane-1,3-diyl;

[0029] R is NR1R2 or phenyl;

[0030] R1 is H;

[0031] R2 is (C1-C6)-alkyl, cyclohexyl or phenyl, wherein said phenylgroup is optionally substituted by F, Cl or (C1-C4)-alkyl;

[0032] R3 is (C3-C6)-cycloalkyl or (C1-C8)-alkyl, each of which isoptionally substituted by phenyl, pyridyl, morpholinyl, cyclopropyl,cyclopentyl, cyclohexyl, and wherein said phenyl substituent isoptionally substituted by chlorine or methyl;

[0033] X is O—CH₂—CH₂;

[0034] Y is OCH₂;

[0035] R4 is H;

[0036] R5 is methyl;

[0037] and pharmaceutically acceptable salts thereof.

[0038] Very particular preference is given to compounds of the formula Iwherein:

[0039] ring A is cyclohexane-1,3-diyl;

[0040] R is NR1R2 or phenyl;

[0041] R1 is H;

[0042] R2 is (C1-C4)-alkyl, cyclohexyl or phenyl, wherein said phenylgroup is optionally substituted by F, Cl or methyl;

[0043] R3 is (C3-C6)-cycloalkyl or (C1-C8)-alkyl, each of which isoptionally substituted by phenyl, pyridyl, morpholinyl, cyclopropyl,cyclopentyl or cyclohexyl, and wherein said phenyl substituent isoptionally substituted by chlorine or methyl;

[0044] X is O—CH₂—CH₂;

[0045] Y is OCH₂;

[0046] R4 is H;

[0047] R5 is methyl;

[0048] and pharmaceutically acceptable salts thereof.

[0049] The link to ring A can be either cis or trans and is preferablycis.

[0050] This invention also encompasses all combinations of preferredaspects of the invention described herein.

[0051] The alkyl radicals in the substituents R1, R2, R3, R4 and R5 maybe either straight-chain or branched.

[0052] Aryl means an aromatic carbocyclic mono- or bicyclic ring systemwhich comprises 6 to 10 atoms in the ring or rings.

[0053] Heteroaryl is a mono- or bicyclic aromatic ring system having 4to 11 ring members, in which at least one atom in the ring system is aheteroatom from the series N, O and S.

[0054] The compounds of the formula I comprise at least two centers ofasymmetry and may comprise more in addition. The compounds of theformula I may therefore exist in the form of their racemates, racemicmixtures, pure enantiomers, diastereomers and mixtures of diastereomers.The present invention encompasses all these isomeric forms of thecompounds of the formula I. These isomeric forms can be obtained byknown methods even if not specifically described in some cases.

[0055] Pharmaceutically acceptable salts are, because their solubilityin water is greater than that of the initial or basic compounds,particularly suitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts), andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

[0056] Salts with a pharmaceutically unacceptable anion such as, forexample, trifluoroacetate likewise belong within the framework of theinvention as useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

[0057] As used herein, the following definitions apply:

[0058] “Patient” means a warm blooded animal, such as for example rat,mice, dogs, cats, guinea pigs, and primates such as humans.

[0059] “Treat” or “treating” means to alleviate symptoms, eliminate thecausation of the symptoms either on a temporary or permanent basis, orto prevent or slow the appearance of symptoms of the named disorder orcondition.

[0060] “Therapeutically effective amount” means a quantity of thecompound which is effective in treating the named disorder or condition.

[0061] “Pharmaceutically acceptable carrier” is a non-toxic solvent,dispersant, excipient, adjuvant or other material which is mixed withthe active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient. One example of such a carrier is apharmaceutically acceptable oil typically used for parenteraladministration.

[0062] The term “physiologically functional derivative” used hereinrefers to any physiologically tolerated derivative of a compound of theformula I of the invention, for example an ester, which onadministration to a mammal such as, for example, a human is able to form(directly or indirectly) a compound of the formula I or an activemetabolite thereof.

[0063] Physiologically functional derivatives also include prodrugs ofthe compounds of the invention, as described, for example, in H. Okadaet al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can bemetabolized in vivo to a compound of the invention. These prodrugs maythemselves be active or not.

[0064] The compounds of the invention may also exist in variouspolymorphous forms, for example as amorphous and crystallinepolymorphous forms. All polymorphous forms of the compounds of theinvention belong within the framework of the invention and are a furtheraspect of the invention.

[0065] All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts,solvates and physiologically functional derivatives as described herein.

[0066] Use

[0067] This invention relates further to the use of compounds of theformula I and their pharmaceutical compositions as PPAR ligands. ThePPAR ligands of the invention are suitable as modulators of PPARactivity.

[0068] Peroxisome proliferator-activated receptors (PPAR) aretranscription factors which can be activated by ligands and belong tothe class of nuclear hormone receptors. There are three PPAR isoforms,PPARalpha, PPARgamma and PPARdelta, which are encoded by different genes(Peroxisome proliferator-activated receptor (PPAR): structure,mechanisms of activation and diverse functions: Motojima K, Cell StructFunct. 1993 October; 18(5): 267-77).

[0069] Two variants of PPARgamma exist, PPARgamma₁ and gamma₂, which arethe result of alternative use of promoters and differential mRNAsplicing (Vidal-Puig et al. J. Clin. Invest., 97:2553-2561,1996).Different PPARs have different tissue distribution and modulatedifferent physiological functions. The PPARs play a key role in variousaspects of the regulation of a large number of genes, the products ofwhich genes are directly or indirectly crucially involved in lipid andcarbohydrate metabolism. Thus, for example, PPARalpha receptors play animportant part in the regulation of fatty acid catabolism or lipoproteinmetabolism in the liver, while PPARgamma is crucially involved forexample in regulating adipose cell differentiation. In addition,however, PPARs are also involved in the regulation of many otherphysiological processes, including those which are not directlyconnected with carbohydrate or lipid metabolism. The activity ofdifferent PPARs can be modulated by various fatty acids, fatty acidderivatives and synthetic compounds to varying extents. For relevantreviews about functions, physiological effect and pathophysiology, see:Joel Berger et al., Annu. Rev. Med. 2002, 53, 409 - 435; Timothy Wilsonet al. J. Med. Chem., 2000, Vol. 43, No.4, 527-550; Steven Kliewer etal., Recent Prog Horm Res. 2001; 56: 239-63.

[0070] The present invention relates to compounds of the formula Isuitable for modulating the activity of PPARs, especially the activityof PPARalpha and PPARgamma. Depending on the modulation profile, thecompounds of the formula I are suitable for the treatment, control andprophylaxis of the indications described hereinafter, and for a numberof other pharmaceutical applications connected thereto (see, forexample, Joel Berger et al., Annu. Rev. Med. 2002, 53, 409-435; TimothyWilson et al. J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; StevenKliewer et al., Recent Prog Horm Res. 2001; 56: 239-63; Jean-CharlesFruchart, Bart Staels and Patrick Duriez: PPARS, Metabolic Disease andArteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52;2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARsin health and disease, NATURE, VOL 405, 25 MAY 2000; 421-4; Ines PinedaTorra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and BartStaels: Peroxisome proliferator-activated receptors: fromtranscriptional control to clinical practice, Curr Opin Lipidol 12:2001, 245-254).

[0071] Compounds of this type are particularly suitable for thetreatment and/or prevention of

[0072] 1.—disorders of fatty acid metabolism and glucose utilizationdisorders

[0073] disorders in which insulin resistance is involved

[0074] 2. Diabetes mellitus, especially type 2 diabetes, including theprevention of the sequelae associated therewith.

[0075] Particular aspects in this connection are

[0076] hyperglycemia,

[0077] improvement in insulin resistance,

[0078] improvement in glucose tolerance,

[0079] protection of the pancreatic β cells

[0080] prevention of macro- and microvascular disorders

[0081] 3. Dyslipidemias and their sequelae such as, for example,atherosclerosis, coronary heart disease, cerebrovascular disorders etc,especially those (but not restricted thereto) which are characterized byone or more of the following factors:

[0082] high plasma triglyceride concentrations, high postprandial plasmatriglyceride concentrations,

[0083] low HDL cholesterol concentrations

[0084] low ApoA lipoprotein concentrations

[0085] high LDL cholesterol concentrations

[0086] small dense LDL cholesterol particles

[0087] high ApoB lipoprotein concentrations

[0088] 4. Various other conditions which may be associated with themetabolic syndrome, such as:

[0089] obesity (excess weight), including central obesity

[0090] thromboses, hypercoagulable and prothrombotic states (arterialand venous)

[0091] high blood pressure

[0092] heart failure such as, for example (but not restricted thereto),following myocardial infarction, hypertensive heart disease orcardiomyopathy

[0093] 5. Other disorders or conditions in which inflammatory reactionsor cell differentiation may for example be involved are:

[0094] atherosclerosis such as, for example (but not restrictedthereto), coronary sclerosis including angina pectoris or myocardialinfarction, stroke

[0095] vascular restenosis or reocclusion

[0096] chronic inflammatory bowel diseases such as, for example, Crohn'sdisease and ulcerative colitis

[0097] pancreatitis

[0098] other inflammatory states

[0099] retinopathy

[0100] adipose cell tumors

[0101] lipomatous carcinomas such as, for example, liposarcomas

[0102] solid tumors and neoplasms such as, for example (but notrestricted thereto), carcinomas of the gastrointestinal tract, of theliver, of the biliary tract and of the pancreas, endocrine tumors,carcinomas of the lungs, of the kidneys and the urinary tract, of thegenital tract, prostate carcinomas etc

[0103] acute and chronic myeloproliferative disorders and lymphomas

[0104] angiogenesis

[0105] neurodegenerative disorders

[0106] Alzheimer's disease

[0107] multiple sclerosis

[0108] Parkinson's disease

[0109] erythemato-squamous dermatoses such as, for example, psoriasis

[0110] acne vulgaris

[0111] other skin disorders and dermatological conditions which aremodulated by PPAR

[0112] eczemas and neurodermitis

[0113] dermatitis such as, for example, seborrheic dermatitis orphotodermatitis

[0114] keratitis and keratoses such as, for example, seborrheickeratoses, senile keratoses, actinic keratosis, photo-induced keratosesor keratosis follicularis

[0115] keloids and keloid prophylaxis

[0116] warts, including condylomata or condylomata acuminata

[0117] human papilloma viral (HPV) infections such as, for example,venereal papillomata, viral warts such as, for example, molluscumcontagiosum, leukoplakia

[0118] papular dermatoses such as, for example, Lichen planus

[0119] skin cancer such as, for example, basal-cell carcinomas,melanomas or cutaneous T-cell lymphomas

[0120] localized benign epidermal tumors such as, for example,keratoderma, epidermal naevi

[0121] chilblains

[0122] high blood pressure

[0123] syndrome X

[0124] polycystic ovary syndrome (PCOS)

[0125] asthma

[0126] osteoarthritis

[0127] lupus erythematosus (LE) or inflammatory rheumatic disorders suchas, for example, rheumatoid arthritis

[0128] vasculitis

[0129] wasting (cachexia)

[0130] gout

[0131] ischemia/reperfusion syndrome

[0132] acute respiratory distress syndrome (ARDS)

[0133] Formulations

[0134] The amount of a compound of formula I necessary to achieve thedesired biological effect depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. The daily doseis generally in the range from 0.001 mg to 100 mg (typically from 0.01mg to 50 mg) per day and per kilogram of bodyweight, for example 0.1-10mg/kg/day. An intravenous dose may be, for example, in the range from0.001 mg to 1.0 mg/kg, which can suitably be administered as infusion of10 ng to 100 ng per kilogram and per minute. Suitable infusion solutionsfor these purposes may contain, for example, from 0.1 ng to 10 mg,typically from 1 ng to 10 mg, per milliliter. Single doses may contain,for example, from 1 mg to 10 g of the active ingredient. Thus, ampulesfor injections may contain, for example, from 1 mg to 100 mg, andsingle-dose formulations which can be administered orally, such as, forexample, capsules or tablets, may contain, for example, from 0.05 to1000 mg, typically from 0.5 to 600 mg. For the therapy of theabovementioned conditions, the compounds of formula I may be used as thecompound itself, but they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, beacceptable in the sense that it is compatible with the other ingredientsof the composition and is not harmful for the patient's health. Thecarrier may be a solid or a liquid or both and is preferably formulatedwith the compound as a single dose, for example as a tablet, which maycontain from 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of formula I. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

[0135] Pharmaceutical compositions of the invention are those suitablefor oral, rectal, topical, peroral (for example sublingual) andparenteral (for example subcutaneous, intramuscular, intradermal orintravenous) administration, although the most suitable mode ofadministration depends in each individual case on the nature andseverity of the condition to be treated and on the nature of thecompound of formula I used in each case. Coated formulations and coatedslow-release formulations also belong within the framework of theinvention. Preference is given to acid- and gastric juice-resistantformulations. Suitable coatings resistant to gastric juice comprisecellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

[0136] Suitable pharmaceutical preparations for oral administration maybe in the form of separate units such as, for example, capsules,cachets, suckable tablets or tablets, each of which contain a definedamount of the compound of formula I; as powders or granules, as solutionor suspension in an aqueous or nonaqueous liquid; or as an oil-in-wateror water-in-oil emulsion. These compositions may, as already mentioned,be prepared by any suitable pharmaceutical method which includes a stepin which the active ingredient and the carrier (which may consist of oneor more additional ingredients) are brought into contact. Thecompositions are generally produced by uniform and homogeneous mixing ofthe active ingredient with a liquid and/or finely divided solid carrier,after which the product is shaped if necessary. Thus, for example, atablet can be produced by compressing or molding a powder or granules ofthe compound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

[0137] Pharmaceutical compositions which are suitable for peroral(sublingual) administration comprise suckable tablets which contain acompound of formula I with a flavoring, normally sucrose and gum arabicor tragacanth, and pastilles which comprise the compound in an inertbase such as gelatin and glycerol or sucrose and gum arabic.

[0138] Pharmaceutical compositions suitable for parenteraladministration comprise preferably sterile aqueous preparations of acompound of formula I, which are preferably isotonic with the blood ofthe intended recipient. These preparations are preferably administeredintravenously, although administration may also take place bysubcutaneous, intramuscular or intradermal injection. These preparationscan preferably be produced by mixing the compound with water and makingthe resulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

[0139] Pharmaceutical compositions suitable for rectal administrationare preferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

[0140] Pharmaceutical compositions suitable for topical use on the skinare preferably in the form of ointment, cream, lotion, paste, spray,aerosol or oil. Carriers which can be used are petrolatum, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration of from 0.1 to 15% by weight of the composition, forexample from 0.5 to 2%.

[0141] Transdermal administration is also possible. Pharmaceuticalcompositions suitable for transdermal uses can be in the form of singleplasters which are suitable for long-term close contact with thepatient's epidermis. Such plasters suitably contain the activeingredient in an aqueous solution which is buffered where appropriate,dissolved and/or dispersed in an adhesive or dispersed in a polymer. Asuitable active ingredient concentration is about 1% to 35%, preferablyabout 3% to 15%. A particular possibility is for the active ingredientto be released by electrotransport or iontophoresis as described, forexample, in Pharmaceutical Research, 2(6): 318 (1986).

[0142] The compounds of the formula I are distinguished by favorableeffects on metabolic disorders. They beneficially influence lipid andsugar metabolism, in particular they lower the triglyceride level andare suitable for the prevention and treatment of type 11 diabetes andarteriosclerosis and the diverse sequalae thereof.

[0143] Combinations with Other Medicaments

[0144] The compounds of the invention can be administered alone or incombination with one or more further pharmacologically active substanceswhich have, for example, favorable effects on metabolic disturbances ordisorders frequently associated therewith. Examples of such medicamentsare

[0145] 1. medicaments which lower blood glucose, antidiabetics,

[0146] 2. active ingredients for the treatment of dyslipidemias,

[0147] 3. antiatherosclerotic medicaments,

[0148] 4. antiobesity agents,

[0149] 5. antiinflammatory active ingredients

[0150] 6. active ingredients for the treatment of malignant tumors

[0151] 7. antithrombotic active ingredients

[0152] 8. active ingredients for the treatment of high blood pressure

[0153] 9. active ingredients for the treatment of heart failure and

[0154] 10. active ingredients for the treatment and/or prevention ofcomplications caused by diabetes or associated with diabetes.

[0155] They can be combined with the compounds of the invention of theformula I in particular for a synergistic improvement in the effect.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

[0156] Examples which may be mentioned are:

[0157] Antidiabetics

[0158] Suitable antidiabetics are disclosed for example in the RoteListe 2001, chapter 12 or in the USP Dictionary of USAN andInternational Drug Names, US Pharmacopeia, Rockville 2001. Antidiabeticsinclude all insulins and insulin derivatives such as, for example,Lantus® (see www.lantus.com) or Apidra®, and other fast-acting insulins(see U.S. Pat. No. 6,221,633), GLP-1 receptor modulators as described inWO 01/04146 or else, for example, those disclosed in WO 98/08871 of NovoNordisk A/S.

[0159] The orally effective hypoglycemic active ingredients include,preferably, sulfonylureas, biguanides, meglitinides,oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors,glucagon antagonists, GLP-1 agonists, DPP-IV inhibitors, potassiumchannel openers such as, for example, those disclosed in WO 97/26265 andWO 99/03861, insulin sensitizers, inhibitors of liver enzymes involvedin the stimulation of gluconeogenesis and/or glycogenolysis, modulatorsof glucose uptake, compounds which alter lipid metabolism and lead to achange in the blood lipid composition, compounds which reduce foodintake, PPAR and PXR modulators and active ingredients which act on theATP-dependent potassium channel of the beta cells.

[0160] In one embodiment of the invention, the compounds of the formulaI are administered in combination with insulin.

[0161] In one embodiment of the invention, the compounds of the formulaI are administered in combination with substances which influencehepatic glucose production such as, for example, glycogen phosphorylaseinhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922,WO 03/104188)

[0162] In one embodiment, the compounds of the formula I areadministered in combination with a sulfonylurea such as, for example,tolbutamide, glibenclamide, glipizide or glimepiride.

[0163] In one embodiment, the compounds of the formula I areadministered in combination with an active ingredient which acts on theATP-dependent potassium channel of the beta cells, such as, for example,tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

[0164] In one embodiment, the compounds of the formula I areadministered in combination with a biguanide such as, for example,mefformin.

[0165] In a further embodiment, the compounds of the formula I areadministered in combination with a meglitinide such as, for example,repaglinide.

[0166] In one embodiment, the compounds of the formula I areadministered in combination with a thiazolidinedione such as, forexample, ciglitazone, pioglitazone, rosiglitazone or the compoundsdisclosed in WO 97/41097 of Dr. Reddy's Research Foundation, inparticular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

[0167] In one embodiment, the compounds of the formula I areadministered in combination with a DPPIV inhibitor as described, forexample, in WO98/19998, WO99/61431, WO99/67278, WO99/67279, WO1/72290,WO 02/38541, WO03/040174, in particular P 93/01(1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98,LAF237(1-[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile),TS021 ((2S,4S)-4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]-acetyl]pyrrolidine-2-carbonitrilemonobenzenesulfonate).

[0168] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a PPARgamma agonist such as, forexample, rosiglitazone, pioglitazone.

[0169] In one embodiment, the compounds of the formula I areadministered in combination with compounds with an inhibitory effect onSGLT-1 and/or 2, as disclosed directly or indirectly for example inPCT/EP03/06841, PCT/EP03/13454 and PCT/EP03/13455.

[0170] In one embodiment, the compounds of the formula I areadministered in combination with an α-glucosidase inhibitor such as, forexample, miglitol or acarbose.

[0171] In one embodiment, the compounds of the formula I areadministered in combination with more than one of the aforementionedcompounds, e.g. in combination with a sulfonylurea and mefformin, asulfonylurea and acarbose, repaglinide and mefformin, insulin and asulfonylurea, insulin and metformin, insulin and troglitazone, insulinand lovastatin, etc.

[0172] Lipid Modulators

[0173] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an HMGCoA reductase inhibitorsuch as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin,itavastatin, atorvastatin, rosuvastatin.

[0174] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a bile acid reabsorptioninhibitor (see, for example, U.S. Pat. Nos. 6,245,744, 6,221,897,6,277,831, EP 0683 773, EP 0683 774).

[0175] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a polymeric bile acid adsorbentsuch as, for example, cholestyramine, colesevelam.

[0176] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a cholesterol absorptioninhibitor as described for example in WO 0250027, or ezetimibe,tiqueside, pamaqueside.

[0177] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an LDL receptor inducer (see, forexample, U.S. Pat. No. 6,342,512).

[0178] In one embodiment, the compounds of the formula I areadministered in combination with bulking agents, preferably insolublebulking agents (see, for example, carob/Caromax® (Zunft H J; et al.,Carob pulp preparation for treatment of hypercholesterolemia, ADVANCESIN THERAPY (2001 September-October), 18(5), 230-6.) Caromax is acarob-containing product from Nutrinova, Nutrition Specialties & FoodIngredients GmbH, Industriepark Höechst, 65926 Frankfurt/Main)).Combination with Caromax® is possible in one preparation or by separateadministration of compounds of the formula I and Caromax®. Caromax® canin this connection also be administered in the form of food productssuch as, for example, in bakery products or muesli bars.

[0179] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a PPARalpha agonist.

[0180] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a mixed PPAR alpha/gamma agonistsuch as, for example, AZ 242 (Tesaglitazar,(S)-3-(4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionicacid), BMS 298585(N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine)or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169,WO96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO00/64876.

[0181] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a fibrate such as, for example,fenofibrate, gemfibrozil, clofibrate, bezafibrate.

[0182] In one embodiment of the invention, the compounds of the formulaI are administered in combination with nicotinic acid or niacin.

[0183] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a CETP inhibitor, e.g. CP-529,414 (torcetrapib).

[0184] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an ACAT inhibitor.

[0185] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an MTP inhibitor such as, forexample, implitapide.

[0186] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an antioxidant.

[0187] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipoprotein lipase inhibitor.

[0188] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an ATP citrate lyase inhibitor.

[0189] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a squalene synthetase inhibitor.

[0190] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipoprotein(a) antagonist.

[0191] Antiobesity Agents

[0192] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipase inhibitor such as, forexample, orlistat.

[0193] In one embodiment, the further active ingredient is fenfluramineor dexfenfluramine.

[0194] In another embodiment, the further active ingredient issibutramine.

[0195] In a further embodiment, the compounds of the formula I areadministered in combination with CART modulators (see“Cocaine-amphetamine-regulated transcript influences energy metabolism,anxiety and gastric emptying in mice” Asakawa, A, et al., M.: Hormoneand Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g.naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}amidehydrochloride (CGP 71683A)), MC4 agonists (e.g.1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide;(WO 01/91752)), orexin antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A)), H3 agonists(3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists,β3 agonists (e.g.1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-ethanolhydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone)agonists, CCK-A agonists (e.g.{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acidtrifluoroacetic acid salt (WO 99/15525)), serotonin reuptake inhibitors(e.g. dexfenfluramine), mixed serotoninergic and noradrenergic compounds(e.g. WO 00/71549), 5HT agonists e.g.1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111),bombesin agonists, galanin antagonists, growth hormone (e.g. humangrowth hormone), growth hormone-releasing compounds(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tertiary butyl ester (WO 01/85695)), TRH agonists (see, forexample, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptinagonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin),lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO00/78312), RXR modulators or TR-β agonists.

[0196] In one embodiment of the invention, the further active ingredientis leptin.

[0197] In one embodiment, the further active ingredient isdexamphetamine, amphetamine, mazindole or phentermine.

[0198] In one embodiment, the compounds of the formula I areadministered in combination with medicaments having effects on thecoronary circulation and the vascular system, such as, for example, ACEinhibitors (e.g. ramipril), medicaments which act on theangiotensin-renine system, calcium antagonists, beta blockers etc.

[0199] In one embodiment, the compounds of the formula I areadministered in combination with medicaments having an antiinflammatoryeffect.

[0200] In one embodiment, the compounds of the formula I areadministered in combination with medicaments which are employed forcancer therapy and cancer prevention.

[0201] It will be appreciated that every suitable combination of thecompounds of the invention with one or more of the aforementionedcompounds and optionally one or more other pharmacologically activesubstances is regarded as falling within the protection conferred by thepresent invention. The activity of the compounds was tested as follows:

[0202] Determination of EC50 Values of PPAR Agonists in the CellularPPARalpha Assay

[0203] Principle

[0204] The potency of substances which bind to human PPARalpha andactivate in an agonistic manner is analyzed using a stably transfectedHEK cell line (HEK=human embryo kidney) which is referred to here asPPARalpha reporter cell line. It contains two genetic elements, aluciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalphafusion protein (GR-GAL4-humanPPARalpha-LBD) which mediates expression ofthe luciferase reporter element depending on a PPARalpha ligand. Thestably and constitutively expressed fusion proteinGR-GAL4-humanPPARalpha-LBD binds in the cell nucleus of the PPARalphareporter cell line via the GAL4 protein portion to the GAL4 DNA bindingmotifs 5′-upstream of the luciferase reporter element which isintegrated in the genome of the cell line. There is only littleexpression of the luciferase reporter gene without addition of aPPARalpha ligand if fatty acid-depleted fetal calf serum (cs-FCS) isused in the assay. PPARalpha ligands bind and activate the PPARalphafusion protein and thereby bring about expression of the luciferasereporter gene. The luciferase which is formed can be detected by meansof chemiluminescence via an appropriate substrate.

[0205] Construction of the Cell Line

[0206] The PPARalpha reporter cell line was prepared in 2 stages.Firstly, the luciferase reporter element was constructed and stablytransfected into HEK cells. For this purpose, five binding sites of theyeast transcription factor GAL4 (each 5′-CGGAGTACTGTCCTCCGAG-3′) (SEQ IDNo. 1) were cloned in 5′-upstream of a 68 bp-long minimal MMTV promoter(Genbank Accession # V01175). The minimal MMTV promoter section containsa CCAAT box and a TATA element in order to enable efficienttranscription by RNA polymerase 11. The cloning and sequencing of theGAL4-MMTV construct took place in analogy to the description of SambrookJ. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press,1989). Then the complete Photinus pyralis gene (Genbank Accession #M15077) was cloned in 3′-downstream of the GAL4-MMTV element. Aftersequencing, the luceriferase reporter element consisting of five GAL4binding sites, MMTV promoter and luciferase gene was recloned into aplasmid which confers zeocin resistance in order to obtain the plasmidpdeltaM-GAL4-Luc-Zeo. This vector was transfected into HEK cells inaccordance with the statements in Ausubel, F. M. et al. (Currentprotocols in molecular biology, Vol. 1-3, John Wiley & Sons, Inc.,1995). Then zeocin-containing medium (0.5 mg/ml) was used to select asuitable stable cell clone which showed very low basal expression of theluceriferase gene. In a second step, the PPARalpha fusion protein(GR-GAL4-humanPPARalpha-LBD) was introduced into the stable cell clonedescribed. For this purpose, initially the cDNA coding for theN-terminal 76 amino acids of the glucocorticoid receptor (GenbankAccession # P04150) was linked to the cDNA section coding for aminoacids 1-147 of the yeast transcription factor GAL4 (Genbank Accession #P04386). The cDNA of the ligand-binding domain of the human PPARalphareceptor (amino acids S167-Y468; Genbank Accession # S74349) was clonedin at the 3′-end of this GR-GAL4 construct. The fusion constructprepared in this way (GR-GAL4-humanPPARalpha-LBD) was recloned into theplasmid pcDNA3 (from Invitrogen) in order to enable constitutiveexpression therein by the cytomegalovirus promoter. This plasmid waslinearized with a restriction endonuclease and stably transfected intothe previously described cell clone containing the luciferase reporterelement. The finished PPARalpha reporter cell line which contains aluciferase reporter element and constitutively expresses the PPARalphafusion protein (GR-GAL4-human PPARalpha-LBD) was isolated by selectionwith zeocin (0.5 mg/ml) and G418 (0.5 mg/ml).

[0207] Assay Procedure

[0208] The activity of PPARalpha agonists is determined in a 3-day assaywhich is described below:

[0209] Day 1

[0210] The PPARalpha reporter cell line is cultivated to 80% confluencein DMEM (# 41965-039, Invitrogen) which is mixed with the followingadditions: 10% cs-FCS (fetal calf serum; #SH-30068.03, Hyclone), 0.5mg/ml zeocin (#R250-01, Invitrogen), 0.5 mg/ml G418 (#10131-027,Invitrogen), 1% penicillin-streptomycin solution (#15140-122,Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Thecultivation takes place in standard cell culture bottles (# 353112,Becton Dickinson) in a cell culture incubator at 37° C. in the presenceof 5% CO₂. The 80%-confluent cells are washed once with 15 ml of PBS(#14190-094, Invitrogen), treated with 3 ml of trypsin solution(#25300-054, Invitrogen) at 37° C. for 2 min, taken up in 5 ml of theDMEM described and counted in a cell counter. After dilution to 500.000cells/ml, 35,000 cells are seeded in each well of a 96 well microtiterplate with a clear plastic base (#3610, Corning Costar). The plates areincubated in the cell culture incubator at 37° C. and 5% CO₂ for 24 h.

[0211] Day 2

[0212] PPARalpha agonists to be tested are dissolved in DMSO in aconcentration of 10 mM. This stock solution is diluted in DMEM(#41965-039, Invitrogen) which is mixed with 5% cs-FCS (#SH-30068.03,Hyclone), 2 mM L-glutamine (#25030-024, Invitrogen) and the previouslydescribed antibiotics (zeocin, G418, penicillin and streptomycin). Testsubstances are tested in 11 different concentrations in the range from10 μM to 100 pM. More potent compounds are tested in concentrationranges from 1 pM to 10 pM or between 100 nM and 1 pM. The medium of thePPARalpha reporter cell line seeded on day 1 is completely removed byaspiration, and the test substances diluted in medium are immediatelyadded to the cells. The dilution and addition of the substances iscarried out by a robot (Beckman FX). The final volume of the testsubstances diluted in medium is 100 μl per well of a 96 well microtiterplate. The DMSO concentration in the assay is less than 0.1 % v/v inorder to avoid cytotoxic effects of the solvent. Each plate was chargedwith a standard PPARalpha agonist, which was likewise diluted in 11different concentrations, in order to demonstrate the functioning of theassay in each individual plate. The assay plates are incubated in anincubator at 37° C. and 5% CO₂ for 24 h.

[0213] Day 3

[0214] The PPARalpha reporter cells treated with the test substances areremoved from the incubator, and the medium is aspirated off. The cellsare lyzed by pipetting 50 μl of Bright Glo reagent (from Promega) intoeach well of a 96 well microtiter plate. After incubation at roomtemperature in the dark for 10 minutes, the microtiter plates aremeasured in the luminometer (Trilux from Wallac). The measuring time foreach well of a microtiter plate is 1 sec.

[0215] Evaluation

[0216] The raw data from the luminometer are transferred into aMicrosoft Excel file. Dose-effect plots and EC50 values of PPAR agonistsare calculated using the XL.Fit program as specified by the manufacturer(IDBS).

[0217] The PPARalpha EC50 values for the compounds of Examples 1 to 62in this assay are in the range from 0.01 nM to >10 μM.

[0218] The results for the activity of some compounds of the inventionof the formula I are indicated in Table I below: TABLE I Example No.EC50 PPARalpha [nM] I 1.9 II 4.9 VII 1.7 VIII 96 IX 0.13 XII 0.07 XV 31XVI 38 XVII 84 XXII 3.3 XXXIX 0.17 XLV 90

[0219] It is evident from Table I that the compounds of the invention ofthe formula I activate the PPARalpha receptor and thus bring about forexample in analogy to fibrates in clinical use a lowering oftriglycerides in the body (see, for example, J.-Ch. Fruchard et al.:PPARS, Metabolic Disease and Atherosclerosis, Pharmacological Research,Vol. 44, No. 5, 345-52, 2001; S. Kersten et al.: Roles of PPARs inhealth and disease, NATURE, VOL 405, 25 MAY 2000, 421-4; I. Pineda etal.: Peroxisome proliferator-activated receptors: from transcriptionalcontrol to clinical practice, Curr Opin Lipidol 12: 2001, 245-254).

[0220] Determination of EC50 values of PPAR agonists in the cellularPPARgamma assay

[0221] Principle

[0222] A transient transfection system is employed to determine thecellular PPARgamma activity of PPAR agonists. It is based on the use ofa luciferase reporter plasmid (pGL3basic-5xGAL4-TK) and of a PPARgammaexpression plasmid (pcDNA3-GAL4-humanPPARgammaLBD). Both plasmids aretransiently transfected into human embryonic kidney cells (HEK cells).There is then expression in these cells of the fusion proteinGAL4-humanPPARgammaLBD which binds to the GAL4 binding sites of thereporter plasmid. In the presence of a PPARgamma-active ligand, theactivated fusion protein GAL4-humanPPARgammaLBD induces expression ofthe luciferase reporter gene, which can be detected in the form of achemiluminescence signal after addition of a luciferase substrate. As adifference from the stably transfected PPARalpha reporter cell line, inthe cellular PPARgamma assay the two components (luciferase reporterplasmid and PPARgamma expression plasmid) are transiently transfectedinto HEK cells because stable and permanent expression of the PPARgammafusion protein is cytotoxic.

[0223] Construction of the Plasmids

[0224] The luciferase reporter plasmid pGL3basic-5xGAL4-TK is based onthe vector pGL3basic from Promega. The reporter plasmid is prepared bycloning five binding sites of the yeast transcription factor GAL4 (eachbinding site with the sequence 5′-CTCGGAGGACAGTACTCCG-3′) (SEQ ID No.2), together with a 160 bp-long thymidine kinase promoter section(Genbank Accession # AF027128) 5′-upstream into pGL3basic. 3′-downstreamof the thymidine kinase promoter is the complete luciferase gene fromPhotinus pyralis (Genbank Accession # M15077) which is already aconstituent of the plasmid pGL3basic used. The cloning and sequencing ofthe reporter plasmid pGL3basic-5xGAL4-TK took place in analogy to thedescription in Sambrook J. et. al. (Molecular cloning, Cold SpringHarbor Laboratory Press, 1989). The PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD was prepared by first cloning the cDNAcoding for amino acids 1-147 of the yeast transcription factor GAL4(Genbank Accession # P04386) into the plasmid pcDNA3 (from Invitrogen)3′-downstream of the cytomegalovirus promoter. Subsequently, the cDNA ofthe ligand-binding domain (LBD) of the human PPARgamma receptor (aminoacids 1152-Y475; Accession # g1480099) 3′-downstream of the GAL4 DNAbinding domain. Cloning and sequencing of the PPARgamma expressionplasmid pcDNA3-GAL4-humanPPARgammaLBD again took place in analogy to thedescription in Sambrook J. et. al. (Molecular cloning, Cold SpringHarbor Laboratory Press, 1989). Besides the luciferase reporter plasmidpGL3basic-5xGAL4-TK and the PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD, also used for the cellular PPARgammaassay are the reference plasmid pRL-CMV (from Promega) and the plasmidpBluescript SK(+) from Stratagene. All four plasmids were prepared usinga plasmid preparation kit from Qiagen, which ensured a plasmid qualitywith a minimal endotoxin content, before transfection into HEK cells.

[0225] Assay Procedure

[0226] The activity of PPARgamma agonists is determined in a 4-day assaywhich is described below. Before the transfection, HEK cells arecultivated in DMEM (# 41965-039, Invitrogen) which is mixed with thefollowing additions: 10% FCS (#16000-044, Invitrogen), 1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen).

[0227] Firstly, solution A, a transfection mixture which contains allfour plasmids previously described in addition to DMEM, is prepared. Thefollowing amounts are used to make up 3 ml of solution A for each 96well microtiter plate for an assay: 2622 pl of antibiotic- and serum4reeDMEM (# 41965-039, Invitrogen), 100 μl of reference plasmid pRL-CMV (1ng/μl), 100 μl of luciferase reporter plasmid pGL3basic-5xGAL4-TK (10ng/μl), 100 μl of PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD (100 ng/μl) and 78 μl of plasmidpBluescript SK(+) (500 ng/μl). Then 2 ml of solution B are prepared bymixing 1.9 ml of DMEM (# 41965-039, Invitrogen) with 100 μl of PolyFecttransfection reagent (from Qiagen) for each 96 well microtiter plate.Subsequently, 3 ml of solution A are mixed with 2 ml of solution B togive 5 ml of solution C, which is thoroughly mixed by multiple pipettingand incubated at room temperature for 10 min. 80%-confluent HEK cellsfrom a cell culture bottle with a capacity of 175 cm² are washed oncewith 15 ml of PBS (#14190-094, Invitrogen) and treated with 3 ml oftrypsin solution (#25300-054, Invitrogen) at 37° C. for 2 min. The cellsare then taken up in 15 ml of DMEM (# 41965-039, Invitrogen) which ismixed with 10% FCS (# 16000-044, Invitrogen), 1% penicillin-streptomycinsolution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024,Invitrogen). After the cell suspension has been counted in a cellcounter, the suspension is diluted to 250,000 cells/ml. 15 ml of thiscell suspension are mixed with 5 ml of solution C for one microtiterplate. 200 μl of the suspension are seeded in each well of a 96 wellmicrotiter plate with a clear plastic base (#3610, Corning Costar). Theplates are incubated in a cell culture incubator at 37° C. and 5% CO₂for 24 h.

[0228] Day 2

[0229] PPAR agonists to be tested are dissolved in DMSO in aconcentration of 10 mM. This stock solution is diluted in DMEM (#41965-039, Invitrogen) which is mixed with 2% Ultroser (#12039-012,Biosepra), 1% penicillin-streptomycin solution (#15140-122, Invitrogen)and 2 mM L-glutamine (#25030-024, Invitrogen). Test substances aretested in a total of 11 different concentrations in the range from 10 μMto 100 pM. More potent compounds are tested in concentration ranges from1 μM to 10 pM.

[0230] The medium of the HEK cells transfected and seeded on day 1 iscompletely removed by aspiration, and the test substances diluted inmedium are immediately added to the cells. The dilution and addition ofthe substances is carried out by a robot (Beckman FX). The final volumeof the test substances diluted in medium is 100 μl per well of a 96 wellmicrotiter plate. Each plate is charged with a standard PPARgammaagonist, which is likewise diluted in 11 different concentrations, inorder to demonstrate the functioning of the assay in each individualplate. The assay plates are incubated in an incubator at 37° C. and 5%CO₂.

[0231] Day 4

[0232] After removal of the medium by aspiration, 50 μl of Dual-Glo™reagent (Dual-Glo™ Luciferase Assay System; Promega) are added to eachwell in accordance with the manufacturer's instructions in order to lyzethe cells and provide the substrate for the firefly luciferase (Photinuspyralis) formed in the cells. After incubation at room temperature inthe dark for 10 minutes, the firefly luciferase-mediatedchemiluminescence is measured in a measuring instrument (measuringtime/well 1 sec; Trilux from Wallac). Then 50 μl of the Dual-Glo™ Stop &Glo reagent (Dual-Glo™ Luciferase Assay System; Promega) is added toeach well in order to stop the activity of the firefly luciferase andprovide the substrate for the Renilla luciferase expressed by thereference plasmid PRL-CMV. After incubation at room temperature in thedark for a further 10 minutes, a chemiluminescence mediated by theRenilla luciferase is again measured for 1 sec/well in the measuringinstrument.

[0233] Evaluation

[0234] The crude data from the luminometer are transferred into aMicrosoft Excel file. The firefly/Renilla luciferase activity ratio isdetermined for each measurement derived from one well of the microtiterplate. The dose-effect plots and EC50 values of PPAR agonists arecalculated from the ratios by the XL.Fit program as specified by themanufacturer (IDBS). PPARgamma EC50 values in the range from 50 nMto >10 μM were measured for the PPAR agonists described in thisapplication.

[0235] The citation of any reference herein should not be construed asan admission that such reference is available as “Prior Art” to theinstant application.

[0236] The present invention is not to be limited in scope by thespecific embodiments describe herein. Indeed, various modifications ofthe invention in addition to those described herein will become apparentto those skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

[0237] Various publications are cited herein, the disclosures of whichare incorporated by reference in their entireties.

[0238] The examples given in Table II serve to illustrate the invention,but without limiting it. TABLE II I

Ex. R- R3- I

II

III

IV

V

VI

VII

VIII

IX

X

XI

XII

XIII

XIV

XV

XVI

XVII

XVIII

XIX

XX

XXI

XXII

XXIII

XXIV

XXV

XXVI

XXVII

XXVIII

XXIX

XXX

XXXI

XXXII

XXXIII

XXXIV

XXXV

XXXVI

XXXVII

XXXVIII

XXXIX

XL

XLI

XLII

XLIII

XLIV

XLV

XLVI

XLVII

XLVIII

XLIX

L

LI

LII

LIII

LIV

LV

LVI

LVII

LVIII

LIX

LX

LXI

LXII

[0239] The compounds of the formula I according to the invention can beobtained according to the reaction scheme below:

[0240] The compound of the general formula A in which n=0-2 is heatedwith dibutyltin oxide in toluene under reflux on a water separator.After addition of cesium fluoride and dimethylformamide, the mixture isreacted with a compound of the general formula B in which R4 and R5 areas defined above and in which x=1-4 to give a compound of the generalformula C in which Y, R4 and R5 are as defined above.

[0241] The compound of the general formula C is converted by stirringwith Candida antarctica lipase B in vinyl acetate at room temperatureinto the enantiomerically pure product of the general formula D. Thecorresponding other enantiomer is removed chromatographically by knownmethods.

[0242] The compound of the general formula C or D is deprotonated withsodium hydride in dimethylformamide or tetrahydrofuran and reacted withan alkenyl bromide of the general formula E in which m=0-2 at roomtemperature to give the racemic (starting from c) or enantiomericallypure (starting from D) compound of the general formula F.

[0243] The respective racemic or enantiomerically pure compound of thegeneral formula F is reacted with sodium periodate and osmium tetroxidein diethyl ether at 0° C. to give the racemic or enantiomerically purealdehyde of the general formula G.

[0244] The compound of the general formula G is reacted with primaryamines R3-NH₂, in which R3 is as defined above, with addition of sodiumborohydride in methanol at room temperature. The ester is hydrolyzed byreacting the substance in a tertiary alcohol (for example tert-butanol)with potassium hydroxide to give the racemic or enantiomerically purecompound of the general formula H in which X is as defined above.

[0245] The compound of the general formula H is reacted with isocyanatesR1-NCO or carbamoyl chlorides R1R2N-COCl or carbonyl chlorides R1-COClin which R1 and R2 are as defined above, to give racemic orenantiomerically pure urea derivatives or carboxamides of the generalformula J in which R, R3, R5, X and Y are as defined above, by stirringboth starting materials in an aprotic solvent (for exampledimethylformamide) at room temperature in the presence of a base (forexample pyridine) for a number of hours.

[0246] Further compounds of the formula I can be preparedcorrespondingly or by known processes.

[0247] The experimental procedures for preparing the examples mentionedabove are described below:

[0248] Examples I-XIV were prepared and tested in enantiomerically pureform.

EXAMPLE I

[0249]

[0250] Methyl 2-(cis-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate

[0251] 8.7 g of 1,3-cyclohexanediol and 12 g of dibutyltin oxide aredissolved in 600 ml of toluene and heated to the boil under reflux on awater separator. During the reaction, the reaction volume is reduced tohalf the original volume. After 4 hours, the reaction mixture is cooledto room temperature and 300 ml of dimethylformamide, 9.0 g of methyl2-bromomethyl-6-methylbenzoate and 9.4 g of cesium fluoride are added.The mixture is stirred at room temperature for 12 hours. The reactionmixture is diluted by addition of ethyl acetate and washed withsaturated sodium chloride solution. The organic phase is dried overmagnesium sulfate, the solvent is reduced under reduced pressure and theresidue is purified by flash chromatography on silica gel(n-heptane/ethyl acetate=50:1→1:2). This gives 6 g of methyl2-(cis-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate as an oil.C16H22O4 (278.35), MS(ESI): 279 (M+H+).

[0252] Methyl 2-((1R,3S)-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate

[0253] 13.1 g of methylcis-2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate are dissolved in100 ml of vinyl acetate and 1.6 g of Candida antartika lipase B areadded. After eight hours of stirring at room temperature, the enzyme isfiltered off and the solvent is removed under reduced pressure. Theresidue is purified by flash chromatography on silica gel(n-heptane/ethyl acetate=10:1→ethyl acetate). This gives 4.3 g of methyl2-((1R,3S)-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate as a colorlessoil. C16H22O4 (278.35), MS(ESI): 279 (M+H+), ee=99% (Chiralpak AD/2250×4.6; n-heptane:ethanol:methanol=25:1:0.5+0.1% trifluoroacetic acid,Rt=8.9 min)

[0254] Methyl 2-((1R,3S)-3-allyloxycyclohexyloxymethyl)-6-methylbenzoate

[0255] 4.3 g of methyl2-((1R,3S)-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate are dissolvedin 40 ml of dimethylformamide and 1.3 g of sodium hydride (60% strengthsuspension in paraffin oil) are added. After 40 minutes of stirring, 4ml of allyl bromide, dissolved in 20 ml of tetrahydrofuran, are added.After 3 hours, 300 ml of ethyl acetate are added and the mixture iswashed three times with saturated sodium chloride solution. The combinedorganic phases are dried over sodium sulfate and the solvents are thenremoved under reduced pressure. The resulting residue is purified onsilica gel using the mobile phase n-heptane:ethyl acetate=50:1→5:1. Thisgives 2.1 g of methyl2-((1R,3S)-3-allyloxycyclohexyloxymethyl)-6-methylbenzoate as a yellowoil. C19H26O4 (318.42), MS(ESI): 319 (M+H+).

[0256] Methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate

[0257] 1.0 g of methyl2-((1R,3S)-3-allyloxycyclohexyloxymethyl)-6-methylbenzoate is dissolvedin 30 ml of diethyl ether, and 2.0 g of sodium periodate, dissolved in30 ml of water, are added. At 0° C., 2 ml of a solution of 2.5% byweight of osmium tetroxide and tert-butanol are added. The reactionmixture is stirred vigorously for three hours. The mixture is thencooled to 0° C., and 50 ml of a saturated sodium thiosulfate solutionare added. The organic phase is removed. The aqueous phase is extractedthree times with in each case 20 ml of diethyl ether. The combinedorganic phases are dried over magnesium sulfate and the solvent is thenremoved under reduced pressure. This gives 1.0 g of methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate as ayellow oil C18H24O5 (320.39), MS(ESI): 321 (M+H+), Rf=0 23(n-heptane:ethyl acetate=1:1).

[0258]2-Methyl-6-{(1R,3S)-3-[2-(3-phenylpropylamino)ethoxy]cyclohexyloxy-methyl}benzoicacid

[0259] 200 mg of methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxy-methyl]benzoate and 90μl of 3-phenylpropylamine are dissolved in 5 ml of methanol. 300 mg of 4A molecular sieve, which had been dried by heating, are added, and themixture is stirred at room temperature for two hours. 25 mg of sodiumborohydride are then added to the reaction mixture. After 30 minutes, 50ml of ethyl acetate are added and the molecular sieve is removed fromthe mixture by filtration through celite. The filtrate is concentratedunder reduced pressure, the residue is dissolved in 5 ml of tert-butanoland 0.5 ml of 10 N potassium hydroxide solution are added. The mixtureis refluxed for 1 day. After addition of 2 ml of water, the organicphase is removed and the aqueous phase is extracted three times with ineach case 20 ml of ethyl acetate. The combined organic phases are driedover magnesium sulfate and the solvents are then removed under reducedpressure. This gives 160 mg of2-methyl-6-{(1R,3S)-3-[2-(3-phenylpropylamino)ethoxy]cyclohexyloxymethyl}benzoicacid as a yellow oil. C26H25NO4 (425.57), MS(ESI): 426 (M+H+).

[0260]2-{(1R,3S)-3-[2-(1-[3-Phenylpropyl]-3-phenylureido)ethoxy]cyclohexyl-oxymethyl}-6-methylbenzoicacid

[0261] 160 mg of2-methyl-6-{(1R,3S)-3-[2-(3-phenylpropylamino)ethoxy]cyclohexyloxymethyl}benzoicacid are dissolved in 2 ml of dimethylformamide, and 0.1 ml of phenylisocyanate is added. After 30 minutes, the reaction mixture is purifiedby RP-HPLC. This gives 54 mg of2-{(1R,3S)-3-[2-(1-[3-phenylpropyl]-3-phenylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid as a white lyophilizate. C33H40N2O5 (544.70), MS(ESI): 545 (M+H+).

EXAMPLE II

[0262] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,2-(4-chlorophenyl)ethylamine and phenyl isocyanate gave2-{(1R,3S)-3-[2-(1-[2-(4-chlorophenyl)ethyl]-3-phenylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0263] C32H37CIN2O5 (565.11), MS(ESI): 565 (M+H+).

EXAMPLE III

[0264] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,3-methylbenzylamine and phenyl isocyanate gave2-{(1R,3S)-3-[2-(1-(3-methylbenzyl)-3-phenyl-ureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0265] C32 H38 N2 O5 (530.66), MS(ESI): 531.

EXAMPLE IV

[0266] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,4-methylbenzylamine and phenyl isocyanate gave2-{(1R,3S)-3-[2-(1-(4-methylbenzyl)-3-phenylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0267] C32 H38 N2 O5 (530.66), MS(ESI): 531.

EXAMPLE V

[0268] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,pyridin-4-ylmethylamine and phenyl isocyanate gave2-{(1R,3S)-3-[2-(1-pyridin-4-ylmethyl-3-phenylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0269] C30 H35 N3 O5 (517.62), MS(ESI): 518.

EXAMPLE VI

[0270] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,3-morpholin4-ylpropylamine and phenyl isocyanate gave2-{(1R,3S)-3-[2-(1-(3-morpholin-4-ylpropyl)-3-phenylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0271] C31 H43 N3 O6 (553.70), MS(ESI): 554.

EXAMPLE VII

[0272] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,pentylamine and phenyl isocyanate gave 2-{(1R,3S)-3-[2-(1-pentyl-3-phenylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0273] C29 H40 N2 O5 (496.64), MS(ESI): 497.

EXAMPLE VIII

[0274] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,2,2-dimethylpropylamine and phenyl isocyanate gave2-((1R,3S)-3-{2-[1-(2,2-dimethylpropyl)-3-phenylureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0275] C29H40N2O5 (496.65), MS(ESI): 497.

EXAMPLE IX

[0276] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,heptylamine and phenyl isocyanate gave2-{(1R,3S)-3-[2-(1-heptyl-3-phenylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0277] C31H44N2O5 (524.71), MS(ESI): 525.

EXAMPLE X

[0278] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclohexylmethylamine and phenyl isocyanate gave2-{(1R,3S)-3-[2-(1-cyclohexylmethyl-3-phenylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0279] C31H42N2O5 (522.69), MS(ESI): 523.

EXAMPLE XI

[0280] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,4-methylbenzylamine and ethyl isocyanate gave2-((1R,3S)-3-{2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}-cyclohexyloxymethyl)-6-methylbenzoic acid.

[0281] C28H38N2O5 (482.63), MS(ESI): 483.

EXAMPLE XII

[0282] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,4-methylbenzylamine and butyl isocyanate gave2-((1R,3S)-3-{2-[3-butyl-1-(4-methylbenzyl)ureido]ethoxy}-cyclohexyloxymethyl)-6-methylbenzoicacid.

[0283] C30H42N2O5 (510.68), MS(ESI): 511.

EXAMPLE XIII

[0284] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,4-methylbenzylamine and cyclohexyl isocyanate gave2-((1R,3S)-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0285] C32H44N2O5 (536.72), MS(ESI): 537.

EXAMPLE XIV

[0286] Analogously to Example I, methyl2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,propylamine and phenyl isocyanate gave2-methyl-6-{(1R,3S)-3-[2-(3-phenyl-1-propylureido)-ethoxy]cyclohexyloxymethyl}benzoicacid.

[0287] C27H36N2O5 (468.60), MS(ESI): 469.

[0288] Examples XV-LXII were prepared and tested as racemic compoundshaving cis configuration of the two substituents on the cyclohexanering.

EXAMPLE XV

[0289] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclohexylamine and 2-methylphenyl isocyanate gave2-{cis-3-[2-(1-cyclohexyl-3-o-tolylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0290] C31 H42N2O5 (522.69), MS(ESI): 523 (M+H+).

EXAMPLE XVI

[0291] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclohexylamine and 3-fluorophenylisocyanate gave2-(cis-3-{2-[1-cyclohexyl-3-(3-fluorophenyl)-ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0292] C30H39FN2O5 (526.65), MS(ESI): 527 (M+H+).

EXAMPLE XVII

[0293] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclohexylamine and butyl isocyanate gave2-{cis-3-[2-(3-butyl-1-cyclohexylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0294] C28H44N2O5 (488.67), MS(ESI): 489 (M+H+).

EXAMPLE XVIII

[0295] Analogously to Example I, racemic methyl2-methyl-6-[cis-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclohexylmethylamine and 2-methyl phenyl isocyanate gave2-{cis-3-[2-(1-cyclohexylmethyl-3-o-tolylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0296] C32H44N2O5 (536.72), MS(ESI): 537 (M+H+).

EXAMPLE XIX

[0297] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclohexylmethylamine and 3-fluorophenylisocyanate gave2-(cis-3-{2-[1-cyclohexylmethyl-3-(3-fluorophenyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0298] C31 H41 FN2O5 (540.68), MS(ESI): 541 (M+H+).

EXAMPLE XX

[0299] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1,3-dimethylbutylamine and 2-methyl phenyl isocyanate gave2-(cis-3-{2-[1-((1R)/(1S),3-dimethylbutyl)-3-o-tolylureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0300] C31H44N2O5 (524.71), MS(ESI): 525 (M+H+).

EXAMPLE XXI

[0301] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1,3-dimethylbutylamine and 3-fluorophenyl isocyanate gave(cis-3-{2-[1-((1S)/(1R),3-dimethylbutyl)-3-(3-fluorophenyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0302] C30H41 FN2O5 (528.67), MS(ESI): 529 (M+H+).

EXAMPLE XXII

[0303] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1,3-dimethyl butylamine and butyl isocyanate gave2-(cis-3-{2-[3-butyl-1-((1 S)/(lR),3-dimethylbutyl)-ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0304] C28H46N2O5 (490.69), MS(ESI): 491 (M+H+).

EXAMPLE XXIII

[0305] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1-ethylpropylamine and 2-methylphenyl isocyanate gave2-(cis-3-{2-[1-(1-ethylpropyl)-3-o-tolylureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0306] C30H42N2O5 (510.68) MS(ESI): 511.

EXAMPLE XXIV

[0307] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1-ethylpropylamine and 3-fluorophenyl isocyanate gave2-(cis-3-{2-[1-(1-ethylpropyl)-3-(3-fluorophenyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0308] C29H39FN2O5 (514.64), MS(ESI): 515 (M+H+).

EXAMPLE XXV

[0309] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1-ethylpropylamine and butyl isocyanate gave2-(cis-3-{2-[3-butyl-1-(1-ethylpropyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0310] C27H44N2O5 (476.66), MS(ESI): 477 (M+H+).

EXAMPLE XXVI

[0311] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1-methylbutylamine and 2-methylphenyl isocyanate gave2-methyl-6-(cis-3-{2-[1(-methylbutyl)-3-o-tolylureido]ethoxy}cyclohexyloxymethyl)benzoicacid.

[0312] C30H42N2O5 (510.68), MS(ESI): 511 (M+H+).

EXAMPLE XXVII

[0313] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1-methylbutylamine and 3-fluorophenylisocyanate gave2-(cis-3-{2-[3-(3-fluorophenyl)-1-(methylbutyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0314] C29H39FN2O5 (514.64), MS(ESI): 515 (M+H+).

EXAMPLE XXVIII

[0315] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,3-methylbenzylamine and 2-methylphenyl isocyanate gave2-methyl-6-(cis-3-{2-[1-(3-methylbenzyl)-3-o-tolylureido]ethoxy}cyclohexyloxymethyl)benzoicacid.

[0316] C33H40N2O5 (544.70), MS(ESI): 545 (M+H+). 544.2937

EXAMPLE XXIX

[0317] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,3-methylbenzylamine and 3-fluorophenyl isocyanate gave2-(cis-3-{2-[3-(3-fluorophenyl)-1-(3-methylbenzyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0318] C32H37FN2O5 (548.66), MS(ESI): 549 (M+H+). 548.2687

EXAMPLE XXX

[0319] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,3-methylbenzylamine and butyl isocyanate gave2-(cis-3-{2-[3-butyl-1-(3-methylbenzyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0320] C30H42N2O5 (510.68), MS(ESI): 511 (M+H+).

EXAMPLE XXXI

[0321] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,2,2-dimethylpropylamine and 2-methylphenylisocyanate gave2-(cis-3-{2-[1-(2,2-d imethylpropyl)-3-o-tolylureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoic acid.

[0322] C30H42N2O5 (510.68), MS(ESI): 511 (M+H+).

EXAMPLE XXXII

[0323] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,2,2-dimethylpropylamine and butyl isocyanate gave2-(cis-3-{2-[3-butyl-1-(2,2-dimethylpropyl)ureido]-ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0324] C27H44N2O5 (476.66), MS(ESI): 477 (M+H+).

EXAMPLE XXXIII

[0325] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,3,3-dimethylbutylamine and 2-methylphenylisocyanate gave2-(cis-3-{2-[1-(3,3-dimethylbutyl)-3-o-tolylureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0326] C31H44N2O5 (524.71), MS(ESI): 525 (M+H+).

EXAMPLE XXXIV

[0327] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,3,3-dimethylbutylamine and 3-fluorophenylisocyanate gave2-(cis-3-{2-[1-(3,3-dimethylbutyl)-3-(3-fluorophenyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0328] C30H41 FN2O5 (528.67), MS(ESI): 529 (M+H+).

EXAMPLE XXXV

[0329] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate, pentylamineand 2-methylphenyl isocyanate gave2-methyl-6-{cis-3-[2-(1-pentyl-3-o-tolylureido)ethoxy]cyclohexyloxymethyl}benzoicacid.

[0330] C30H42N2O5 (510.68), MS(ESI): 511 (M+H+).

EXAMPLE XXXVI

[0331] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate, heptylamineand 2-methylphenyl isocyanate gave2-{cis-3-[2-(1-heptyl-3-o-tolylureido)ethoxy]cyclohexyloxy-methyl}-6-methylbenzoicacid.

[0332] C32H46N2O5 (538.73), MS(ESI): 539 (M+H+).

EXAMPLE XXXVII

[0333] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate, heptylamineand 3-fluorophenyl isocyanate gave2-(cis-3-{2-[3-(3-fluorophenyl)-1-heptylureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0334] C31H43FN2O5 (542.70), MS(ESI): 543 (M+H+).

EXAMPLE XXXVIII

[0335] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate, heptylamineand 4-fluorophenyl isocyanate gave2-(cis-3-{2-[3-(4-fluorophenyl)-1-heptylureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0336] C31 H43FN2O5 (542.70), MS(ESI): 542 (M+H+).

EXAMPLE XXXIX

[0337] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate, heptylamineand butyl isocyanate gave2-{cis-3-[2-(3-butyl-1-heptylureido)ethoxy]cyclohexyloxy-methyl}-6-methylbenzoicacid.

[0338] C29H48N2O5 (504.72), MS(ESI): 505 (M+H+).

EXAMPLE XL

[0339] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1,2-dimethylpropylamine and 2-methylphenylisocyanate gave2-(cis-3-{2-[1-((1R)/(1S),2-dimethylpropyl)-3-o-tolylureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0340] C30H42N2O5 (510.68), MS(ESI): 567 (M+H+).

EXAMPLE XLI

[0341] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1,2-dimethylpropylamine and 3-fluorophenylisocyanate gave2-(cis-3-{2-[1-(2-dimethylpropyl)-3-(3-fluorophenyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0342] C29H39FN2O5 (514.64), MS(ESI): 515 (M+H+).

EXAMPLE XLII

[0343] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1,2-dimethylpropylamine and 4-fluorophenylisocyanate gave2-(cis-3-{2-[1-(2-dimethylpropyl)-3-(4-fluorophenyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0344] C29H39FN2O5 (514.64), MS(ESI): 515 (M+H+).

EXAMPLE XLIII

[0345] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,1,2-dimethylpropylamine and butyl isocyanate gave2-(cis-3-{2-[3-butyl-1-(2-dimethylpropyl)ureido]-ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0346] C27H44N2O5 (476.66), MS(ESI): 477 (M+H+).

EXAMPLE XLIV

[0347] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclopropylamine and 2-methylphenyl isocyanate gave2-{cis-3-[2-(1-cyclopropyl-3-o-tolylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0348] C28H36N2O5 (480.61), MS(ESI): 481 (M+H+).

EXAMPLE XLV

[0349] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclopropylamine and 3-fluorophenyl isocyanate gave2-(cis-3-{2-[1-cyclopropyl-3-(3-fluorophenyl)-ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0350] C27H33FN2O5 (484.57), MS(ESI): 485 (M+H+).

EXAMPLE XLVI

[0351] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclopropylamine and 4-fluorophenyl isocyanate gave2-(cis-3-{2-[1-cyclopropyl-3-(4-fluorophenyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0352] C27H33FN2O5 (484.57), MS(ESI): 485 (M+H+).

EXAMPLE XLVII

[0353] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclopropylamine and butyl isocyanate gave2-{cis-3-[2-(3-butyl-1-cyclopropylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0354] C25H38N2O5 (446.59), MS(ESI): 447 (M+H+).

EXAMPLE XLVIII

[0355] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate, benzylamineand 2-methylphenylisocyanate gave2-{cis-3-[2-(1-benzyl-3-o-tolylureido)ethoxy]-cyclohexyloxymethyl}-6-methylbenzoicacid.

[0356] C32H38N2O5 (530.67), MS(ESI): 531 (M+H+).

EXAMPLE XLIX

[0357] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate, benzylamineand 3-fluorophenyl isocyanate gave2-(cis-3-{2-[1-benzyl-3-(3-fluorophenyl)ureido]ethoxy}-cyclohexyloxymethyl)-6-methylbenzoicacid.

[0358] C31H35FN2O5 (534.63), MS(ESI): 535 (M+H+).

EXAMPLE L

[0359] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate, benzylamineand 4-fluorophenyl isocyanate gave2-(cis-3-{2-[1-benzyl-3-(4-fluorophenyl)ureido]ethoxy}-cyclohexyloxymethyl)-6-methylbenzoicacid.

[0360] C31H35FN2O5 (534.63), MS(ESI): 535 (M+H+).

EXAMPLE LI

[0361] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate, benzylamineand butyl isocyanate gave2-{cis-3-[2-(1-benzyl-3-butylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0362] C29H40N2O5 (496.65), MS(ESI): 497 (M+H+).

EXAMPLE LII

[0363] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,pyridin-4-ylmethylamine and 2-methylphenyl isocyanate gave2-methyl-6-{cis-3-[2-(1-pyridin-3-ylmethyl-3-o-tolylureido)ethoxy]cyclohexyloxymethyl}benzoicacid trifluoroacetate.

[0364] C31H37N3O5.C2HF3O2 (645.68), MS(ESI): 532 (M+H+).

EXAMPLE LIII

[0365] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,pyridin-4-ylmethylamine and 3-fluorophenylisocyanate gave2-(cis-3-{2-[3-(3-fluorophenyl )-1-pyridin-3-ylmethylureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoic acidtrifluoroacetate.

[0366] C30H35N3O5.C2HF23O2 (649.64), MS(ESI): 536 (M+H+).

EXAMPLE LIV

[0367] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,pyridin-4-ylmethylamine and 4-fluorophenylisocyanate gave2-(cis-3-{2-[3-(4-fluorophenyl)-1-pyridin-3-ylmethylureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid trifluoroacetate.

[0368] C30H34FN3O5.C2HF3O2 (649.64); MS(ESI): 536 (M+H+).

EXAMPLE LV

[0369] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,pyridin-4-ylmethylamine and butyl isocyanate gave2-{cis-3-[2-(3-butyl-1-pyridin-3-ylmethylureido)-ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid trifluoroacetate.

[0370] C28H39N3O5.C2HF3O2 (611.66), MS(ESI): 498 (M+H+).

EXAMPLE LVI

[0371] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,2-methylbutylamine and 3-fluorophenyl isocyanate gave2-(cis-3-{2-[3-(3-fluorophenyl)-1-(2-methylbutyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0372] C29H39FN2O5 (514.643), MS(ESI): 515 (M+H+).

EXAMPLE LVII

[0373] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,2-methylbutylamine and 4-fluorophenyl isocyanate gave2-(cis-3-{2-[3-(4-fluorophenyl)-1-(2-methylbutyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0374] C29H39FN2O5 (514.64), MS(ESI): 515 (M+H+).

EXAMPLE LVIII

[0375] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclopentylamine and 2-methylphenyl isocyanate gave2-{cis-3-[2-(1-cyclopentyl-3-o-tolylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0376] C30H40N2O5 (508.66), MS(ESI): 509 (M+H+).

EXAMPLE LIX

[0377] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclopentylamine and 3-fluorophenylisocyanate gave2-(cis-3-{2-[1-cyclopentyl-3-(3-fluorophenyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0378] C29H37FN2O5 (512.62), MS(ESI): 513 (M+H+).

EXAMPLE LX

[0379] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclopentylamine and 4-fluorophenyl isocyanate gave2-(cis-3-{2-[1-cyclopentyl-3-(4-fluorophenyl)ureido]ethoxy}cyclohexyloxymethyl)-6-methylbenzoicacid.

[0380] C29H37FN2O5 (512.62), MS(ESI): 513 (M+H+).

EXAMPLE LXI

[0381] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,cyclopentylamine and butyl isocyanate gave2-{cis-3-[2-(3-butyl-1-cyclopentylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoicacid.

[0382] C27H42N2O5 (474.65), MS(ESI): 475 (M+H+).

EXAMPLE LXII

[0383] Analogously to Example I, racemic methyl2-methyl-6-[cis-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate,2-chlorobenzylamine and benzoyl chloride gave2-(cis-3-{2-[benzoyl-(2-chlorobenzyl)amino]ethoxy}-cyclohexyloxymethyl)-6-methylbenzoicacid.

[0384] C31 H34CINO5 (536.07), MS(ESI): 536 (M+H+).

1 2 1 19 DNA Artificial Binding Site of Yeast Transcription Factor GAL41 cggagtactg tcctccgag 19 2 19 DNA Artificial Binding Site of YeastTranscription Factor GAL4 2 ctcggaggac agtactccg 19

We claim:
 1. A compound of the formula I

wherein ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl,wherein one or more carbon atoms in said (C3-C8)-cycloalkanediyl and(C3-C8)-cycloalkenediyl groups are optionally replaced by oxygen atoms;R is NR1R2 or OR1, (C6-C10)-aryl or (C5-C12)-heteroaryl, wherein said(C5-C12)-heteroaryl group contains one, two or three identical ordifferent heteroatoms selected from the group consisting of N, O and S;R1 , R2 are each independently H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or(C6-C10)-aryl, wherein said (C6-C10)-aryl is optionally substituted byF, Cl or (C1-C4)-alkyl; R3 is (C3-C6)-cycloalkyl or (C1-C10)-alkyl,wherein each group is optionally substituted by phenyl, pyridyl,morpholinyl or (C3-C6)-cycloalkyl, and wherein said phenyl substituentis optionally substituted by chlorine or (C1-C4)-alkyl; X is(C1-C6)-alkanediyl, wherein one or more carbon atoms therein areoptionally replaced by oxygen atoms; Y is (C1-C6)-alkanediyl, whereinone or more carbon atoms therein are optionally replaced by oxygenatoms; R4 is H or (C1-C4)-alkyl; R5 is (C1-C4)-alkyl; andpharmaceutically acceptable salts thereof.
 2. The compound of claim 1wherein: ring A is (C3-C8)-cycloalkane-1,3-diyl or(C3-C8)-cycloalkene-1,3-diyl; R is NR1R2 or (C6-C10)-aryl; R1 , R2 areeach independently H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or(C6-C10)-aryl, wherein said (C6-C10)-aryl group is optionallysubstituted by F, Cl or (C1-C4)-alkyl; R3 is (C3-C6)-cycloalkyl or(C1-C8)-alkyl, wherein each group is optionally substituted by phenyl,pyridyl, morpholinyl, (C3-C6)-cycloalkyl, and wherein said phenylsubstituent is optionally substituted by chlorine or methyl; X is(C1-C3)-alkanediyl, wherein one carbon atom therein is optionallyreplaced by an oxygen atom; Y is (C1-C3)-alkanediyl, wherein the carbonatom adjacent to ring A in said (C1-C3)-alkanediyl group is optionallyreplaced by an oxygen atom; R4 is H; R5 is methyl; and pharmaceuticallyacceptable salts thereof.
 3. The compound of claim 2 wherein: ring A iscyclohexane-1,3-diyl; R is NR1R2 or phenyl; R1 is H; R2 is(C1-C6)-alkyl, cyclohexyl or phenyl, wherein said phenyl group isoptionally substituted by F, Cl or (C1-C4)-alkyl; R3 is(C3-C6)-cycloalkyl or (C1-C8)-alkyl, each of which is optionallysubstituted by phenyl, pyridyl, morpholinyl, cyclopropyl, cyclopentyl,cyclohexyl, and wherein said phenyl substituent is optionallysubstituted by chlorine or methyl; X is O—CH₂—CH₂; Y is OCH₂; R4 is H;R5 is methyl; and pharmaceutically acceptable salts thereof.
 4. Thecompound of claim 3 wherein: ring A is cyclohexane-1,3-diyl; R is NR1R2or phenyl; R1 is H; R2 is (C1-C4)-alkyl, cyclohexyl or phenyl, whereinsaid phenyl group is optionally substituted by F, Cl or methyl; R3 is(C3-C6)-cycloalkyl or (C1-C8)-alkyl, each of which is optionallysubstituted by phenyl, pyridyl, morpholinyl, cyclopropyl, cyclopentyl orcyclohexyl, and wherein said phenyl substituent is optionallysubstituted by chlorine or methyl; X is O—CH₂—CH₂; Y is OCH₂; R4 is H;R5 is methyl; and pharmaceutically acceptable salts thereof.
 5. Thecompound of claim 4 wherein the link of X and Y to ring A iscis-configured.
 6. A pharmaceutical composition comprising apharmaceutically acceptable carrier and one or more compounds ofclaim
 1. 7. The pharmaceutical composition of claim 8 further comprisingat least one additional active ingredient.
 8. The pharmaceuticalcomposition of claim 7 wherein said additional active ingredient hasfavorable effects on metabolic disturbances or disorders.
 9. Thepharmaceutical composition of claim 7 wherein said additional activeingredient is an antidiabetic.
 10. The pharmaceutical composition ofclaim 7 wherein said additional active ingredient is a lipid modulator.11. A method of treating disorders of fatty acid metabolism and glucoseutilization comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim
 1. 12. A methodof treating disorders of insulin resistence comprising administering toa patient in need thereof a therapeutically effective amount of acompound of claim
 1. 13. A method of treating diabetes mellitusincluding the prevention of the squelae associated therewith comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim
 1. 14. A method of treating dyslipidemiaand squelae associated therewith comprising administering to a patientin need thereof a therapeutically effective amount of a compound ofclaim
 1. 15. A method of treating metabolic syndrome and conditionsassociated therewith comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim
 1. 16.A method of treating disorders of fatty acid metabolism and glucoseutilization comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1 in combinationwith at least one further active compound.
 17. A method of treatingdisorders of insulin resistance comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of claim 1in combination with at least one further active compound.